title: (-)-Xanthatin induces the prolonged expression of c-Fos through an N-acetyl-L-cysteine (NAC)-sensitive mechanism in human breast cancer MDA-MB-231 cells.
abstract: We reported that (-)-xanthatin, a xanthanolide sesquiterpene lactone present in the Cocklebur plant, exhibited potent anti-proliferative effects on human breast cancer cells, in which GADD45γ, a novel tumor suppressor gene, was induced. Mechanistically, topoisomerase IIα (Topo IIα) inhibition by (-)-xanthatin was shown to be the upstream trigger that stimulated the expression of GADD45γ mRNA and concomitantly produced reactive oxygen species (ROS) to maintain this expression. Since the anti-cancer drug etoposide, a selective Topo IIα inhibitor, has also been shown to induce intracellular ROS, (-)-xanthatin may exert its anti-proliferative effects on cancer cells in a similar manner to those of etoposide. In the present study, to generalize its applicability to cancer therapy, we further investigated the biological activities of (-)-xanthatin by comparing its activities to those of the established anti-cancer drug etoposide. After the exposure of breast cancer cells to (-)-xanthatin or etoposide, a prolonged and marked up-regulation in the expression of c-fos, a proapoptotic molecule, was detected together with GADD45γ; and the expression of these molecules was stabilized by ROS and abrogated by the pretreatment with N-acetyl-L-cysteine (NAC), a potent ROS scavenger. (-)-Xanthatin in particular exhibited stronger anti-proliferative potential than that of etoposide, which underlies the marked induction of c-fos/GADD45γ and ROS production.
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, Japan.
authors.forename: Shuso
authors.initials: S
authors.lastname: Takeda
authors.forename: Hajime
authors.initials: H
authors.lastname: Nishimura
authors.forename: Kuniyoshi
authors.initials: K
authors.lastname: Koyachi
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Yoshida
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Amamoto
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shindo
authors.forename: Hironori
authors.initials: H
authors.lastname: Aramaki
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000235:genetics*; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000097642:GADD45 Proteins
chemical_list: D000111:Acetylcysteine; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D005047:Etoposide; D016166:Free Radical Scavengers; D005663:Furans; D047908:Intracellular Signaling Peptides and Proteins; D016760:Proto-Oncogene Proteins c-fos; D017382:Reactive Oxygen Species; D000097642:GADD45 Proteins; C022186:xanthatin